The shape of desmosomal cadherins (blue) can be seen using electron tomography.

Stokes/AAAS

Intermediate filament–associated desmosomes—like their actin-associated counterparts, adherens junctions—link neighboring epithelial cells through cadherin connections. Crystal structure analyses of adherens junction cadherins suggested that these proteins interact at their NH2-terminal tips. A recent model shows that the most distal of five extracellular domains, called EC1, contains a tryptophan that can nestle in a hydrophobic pocket of an opposing cadherin's EC1. Other studies suggested that strong adhesion could only be produced by more extensive interactions along the extracellular arms.

Using electron tomography—EM with tilting to give three-dimensional information—Wanzhong He, Pamela Cowin, and David Stokes (New York University, New York, NY) now get a better view of EC1 interactions and other cadherin contacts in desmosomes.

The tomographical maps revealed that the cadherins adopt geometries resembling the letters S, W, and λ. Based on the crystal structure of a classical cadherin, the authors conclude that the desmosomal shapes are evidence of flexible EC1-type interactions. W represents two cadherins from neighboring cells interacting at their NH2-terminal tips, each with its EC1 Trp caught in the hydrophobic pocket of the other. An S shape results if the Trp from one cadherin escapes, and its NH2 terminus rotates. If this now free Trp is captured by the hydrophobic pocket of a third cadherin (this time on the same cell), the resulting shape resembles λ.

The authors also noted that cadherins do not form regular zipper-like arrangements, as commonly depicted for classical cadherins. Desmosomal cadherins assemble into knots formed by groups of 10–20 molecules with their NH2-terminal domains midway between the two cells. The authors believe that these larger groupings may be initiated by EC1 interactions, but in a more random and dynamic fashion than shown by crystal structures. “It's not a regular, rigid, ordered arrangement,” says Stokes. “The mechanism of cadherin interactions allows for specific interactions, but others get tangled in this mess. The key is visualizing this within junctions,” he says, rather than in the artificial crystal structure. ▪